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Alecensa Epar Product Information en
Alecensa Epar Product Information en
1
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
3. PHARMACEUTICAL FORM
Hard capsule.
White hard capsule of 19.2 mm length, with “ALE” printed in black ink on the cap and “150 mg”
printed in black ink on the body.
4. CLINICAL PARTICULARS
Alecensa as monotherapy is indicated for the first-line treatment of adult patients with anaplastic
lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).
Alecensa as monotherapy is indicated for the treatment of adult patients with ALK-positive advanced
NSCLC previously treated with crizotinib.
Treatment with Alecensa should be initiated and supervised by a physician experienced in the use of
anticancer medicinal products.
A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. ALK-positive
NSCLC status should be established prior to initiation of Alecensa therapy.
Posology
The recommended dose of Alecensa is 600 mg (four 150 mg capsules) taken twice daily with food
(total daily dose of 1200 mg).
Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of
450 mg taken twice daily with food (total daily dose of 900 mg).
Duration of treatment
Treatment with Alecensa should be continued until disease progression or unacceptable toxicity.
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Delayed or missed doses
If a planned dose of Alecensa is missed, patients can make up that dose unless the next dose is due
within 6 hours. Patients should not take two doses at the same time to make up for a missed dose. If
vomiting occurs after taking a dose of Alecensa, patients should take the next dose at the scheduled
time.
Dose adjustments
Management of adverse events may require dose reduction, temporary interruption, or discontinuation
of treatment with Alecensa. The dose of Alecensa should be reduced in steps of 150 mg twice daily
based on tolerability. Alecensa treatment should be permanently discontinued if patients are unable to
tolerate the 300 mg twice daily dose.
Table 2 Dose modification advice for specified Adverse Drug Reactions (see sections 4.4 and 4.8)
ALT or AST elevation of Grade ≥ 3 (> 5 times Temporarily withhold until recovery to baseline or
ULN) with total bilirubin ≤ 2 times ULN ≤ Grade 1 (≤ 3 times ULN), then resume at
reduced dose (see Table 1).
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CTCAE grade Alecensa treatment
CPK elevation > 5 times ULN Temporarily withhold until recovery to baseline or
to ≤ 2.5 times ULN, then resume at the same dose.
CPK elevation > 10 times ULN or second Temporarily withhold until recovery to baseline or
occurrence of CPK elevation of > 5 times ULN to ≤ 2.5 times ULN, then resume at reduced dose
as per Table 1.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; CTCAE =
NCI Common Terminology Criteria for Adverse Events; ILD = interstitial lung disease; ULN = upper limit of
normal
a
Heart rate less than 60 beats per minute (bpm).
Special populations
Hepatic impairment
No starting dose adjustment is required in patients with underlying mild (Child-Pugh A) or moderate
(Child-Pugh B) hepatic impairment. Patients with underlying severe hepatic impairment (Child-Pugh
C) should receive a starting dose of 450 mg taken twice daily (total dose of 900 mg) (see section 5.2).
For all patients with hepatic impairment, appropriate monitoring (e.g. markers of liver function) is
advised, see section 4.4.
Renal impairment
No dose adjustment is required in patients with mild or moderate renal impairment. Alecensa has not
been studied in patients with severe renal impairment. However, since alectinib elimination via the
kidney is negligible, no dose adjustment is required in patients with severe renal impairment (see
section 5.2).
Elderly (≥ 65 years)
The limited data on the safety and efficacy of Alecensa in patients aged 65 years and older do not
suggest that a dose adjustment is required in elderly patients (see section 5.2). There are no available
data on patients over 80 years of age.
Paediatric population
The safety and efficacy of Alecensa in children and adolescents below 18 years of age have not been
established. No data are available.
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Extreme body weight (>130 kg)
Although PK simulations for Alecensa do not indicate a low exposure in patients with extreme body
weight (i.e. >130 kg), alectinib is widely distributed and clinical studies for alectinib enrolled patients
within a range of body weights of 36.9−123 kg. There are no available data on patients with body
weight above 130 kg.
Method of administration
Alecensa is for oral use. The hard capsules should be swallowed whole, and must not be opened or
dissolved. They must be taken with food (see section 5.2).
4.3 Contraindications
Hepatotoxicity
Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than
5 times the ULN as well as bilirubin elevations of more than 3 times the ULN occurred in patients in
pivotal clinical trials with Alecensa (see section 4.8). The majority of these events occurred during the
first 3 months of treatment. In the pivotal Alecensa clinical trials it was reported that three patients
with Grade 3-4 AST/ALT elevations had drug induced liver injury. Concurrent elevations in ALT or
AST greater than or equal 3 times the ULN and total bilirubin greater than or equal 2 times the ULN,
with normal alkaline phosphatase, occurred in one patient treated in Alecensa clinical trials.
Liver function, including ALT, AST, and total bilirubin should be monitored at baseline and then
every 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performed
periodically, since events may occur later than 3 months, with more frequent testing in patients who
develop aminotransferase and bilirubin elevations. Based on the severity of the adverse drug reaction,
Alecensa should be withheld and resumed at a reduced dose, or permanently discontinued as described
in Table 2 (see section 4.2).
Elevations of CPK occurred in pivotal trials with Alecensa, including Grade 3 events (see section 4.8).
Median time to Grade 3 CPK elevation was 14 days across clinical trials (NP28761, NP28673,
BO28984).
Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK
levels should be assessed every two weeks for the first month of treatment and as clinically indicated
in patients reporting symptoms. Based on the severity of the CPK elevation, Alecensa should be
withheld, then resumed or dose reduced (see section 4.2).
Bradycardia
Symptomatic bradycardia can occur with Alecensa (see section 4.8). Heart rate and blood pressure
should be monitored as clinically indicated. Dose modification is not required in case of asymptomatic
bradycardia (see section 4.2). If patients experience symptomatic bradycardia or life-threatening
events, concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive
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medicinal products should be evaluated and Alecensa treatment should be adjusted as described in
Table 2 (see sections 4.2 and 4.5, ‘P-gp substrates’ and ‘BCRP substrates’).
Photosensitivity
Photosensitivity to sunlight has been reported with Alecensa administration (see section 4.8). Patients
should be advised to avoid prolonged sun exposure while taking Alecensa, and for at least 7 days after
discontinuation of treatment. Patients should also be advised to use a broad-spectrum Ultraviolet A
(UVA)/ Ultraviolet B (UVB) sun screen and lip balm (SPF ≥50) to help protect against potential
sunburn.
Lactose intolerance
This medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, a congenital lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Sodium content
This medicinal product contains 48 mg sodium per daily dose (1200 mg), equivalent to 2.4% of the
WHO recommended maximum daily intake of 2 g sodium for an adult.
4.5 Interaction with other medicinal products and other forms of interaction
CYP3A inducers
Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer,
with a single oral dose of 600 mg alectinib reduced alectinib Cmax, and AUCinf by 51% and 73%
respectively and increased M4 Cmax and AUCinf 2.20 and 1.79-fold respectively. The effect on the
combined exposure of alectinib and M4 was minor, reducing Cmax and AUCinf by 4% and 18%,
respectively. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments
are required when Alecensa is co-administered with CYP3A inducers. Appropriate monitoring is
recommended for patients taking concomitant strong CYP3A inducers (including, but not limited to,
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum
perforatum)).
CYP3A inhibitors
Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A
inhibitor, with a single oral dose of 300 mg alectinib increased alectinib exposure Cmax and AUCinf by
1.18 and 1.75-fold respectively, and reduced M4 Cmax and AUCinf by 71% and 25% respectively.The
effect on the combined exposure of alectinib and M4 was minor, reducing Cmax by 7% and increasing
AUCinf 1.36-fold. Based on the effects on the combined exposure of alectinib and M4, no dose
adjustments are required when Alecensa is co-administered with CYP3A inhibitors. Appropriate
monitoring is recommended for patients taking concomitant strong CYP3A inhibitors (including, but
not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole,
posaconazole nefazodone, grapefruit or Seville oranges).
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adjustments are required when Alecensa is co-administered with proton pump inhibitors or other
medicinal products which raise gastric pH (e.g. H2 receptor antagonists or antacids).
P-gp substrates
In vitro, alectinib and its major active metabolite M4 are inhibitors of the efflux transporter
P-glycoprotein (P-gp). Therefore, alectinib and M4 may have the potential to increase plasma
concentrations of co-administered substrates of P-gp. When Alecensa is co-administered with P-gp
substrates (e.g., digoxin, dabigatran etexilate, topotecan, sirolimus, everolimus, nilotinib and
lapatinib), appropriate monitoring is recommended.
BCRP substrates
In vitro, alectinib and M4 are inhibitors of the efflux transporter Breast Cancer Resistance Protein
(BCRP). Therefore, alectinib and M4 may have the potential to increase plasma concentrations of
co-administered substrates of BCRP. When Alecensa is co-administered with BCRP substrates (e.g.,
methotrexate, mitoxantrone, topotecan and lapatinib), appropriate monitoring is recommended.
CYP substrates
In vitro, alectinib and M4 show weak time-dependent inhibition of CYP3A4, and alectinib exhibits a
weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations.
Multiple doses of 600 mg alectinib had no influence on the exposure of midazolam (2 mg), a sensitive
CYP3A substrate. Therefore, no dose adjustment is required for co-administered CYP3A substrates.
A risk for induction of CYP2B6 and PXR regulated enzymes apart from CYP3A4 cannot be
completely excluded. The effectiveness of concomitant administration of oral contraceptives may be
reduced.
Pregnancy
There are no or limited amount of data from the use of Alecensa in pregnant women. Based on its
mechanism of action, Alecensa may cause foetal harm when administered to a pregnant woman.
Studies in animals have shown reproductive toxicity (see section 5.3).
Female patients, who become pregnant while taking Alecensa or during the 3 months following the
last dose of Alecensa must contact their doctor and should be advised of the potential harm to the
foetus.
Breast-feeding
It is unknown whether alectinib and its metabolites are excreted in human milk. A risk to the
newborn/infant cannot be excluded. Mothers should be advised against breast-feeding while receiving
Alecensa.
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Fertility
No fertility studies in animals have been performed to evaluate the effect of Alecensa. No adverse
effects on male and female reproductive organs were observed in general toxicology studies (see
section 5.3).
Alecensa has minor influence on the ability to drive and use machines. Caution should be exercised
when driving or operating machines as patients may experience symptomatic bradycardia (e.g.,
syncope, dizziness, hypotension) or vision disorders while taking Alecensa (see section 4.8).
The data described below reflect exposure to Alecensa in 405 patients with ALK-positive advanced
NSCLC who participated in one randomised Phase III clinical trial (BO28984) and in two single-arm
phase II clinical trials (NP28761, NP28673). These patients were treated with the recommended dose
of 600 mg twice daily. In the phase II clinical trials (NP28761, NP28673; N=253), the median
duration of exposure to Alecensa was 11 months. In BO28984 (ALEX; N=152) the median duration of
exposure to Alecensa was 17.9 months, whereas the median duration of exposure to crizotinib was
10.7 months.
The most common adverse drug reactions (ADRs) (≥ 20%) were constipation (35%), oedema (30%,
including oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema, face
oedema and localised oedema), and myalgia (28%, including myalgia and musculoskeletal pain).
The ADRs listed in Table 3 are presented by system organ class and frequency categories, defined
using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon
(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each system organ
class, undesirable effects are presented in order of decreasing frequency.
Table 3 ADRs reported in Alecensa clinical trials (NP28761, NP28673, BO28984; N=405) and
during post-marketing
System organ class Alecensa
ADRs (MedDRA) N=405
All grades Frequency category Grades 3-4
(%) (all grades) (%)
Blood and lymphatic system disorders
Anaemia1) 17 Very common 3.0
Nervous system disorders
Dysgeusia 2) 5.2 Common 0.2
Eye disorders
Vision disorders3) 8.6 Common 0
Cardiac disorders
Bradycardia4) 8.9 Common 0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease / 0.7 Uncommon 0.2
pneumonitis
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System organ class Alecensa
ADRs (MedDRA) N=405
All grades Frequency category Grades 3-4
(%) (all grades) (%)
Gastrointestinal disorders
Constipation 35 Very common 0
Nausea 19 Very common 0.5
Diarrhoea 16 Very common 0.7
Vomiting 11 Very common 0.2
5)
Stomatitis 3.0 Common 0
Hepatobiliary disorders
Increased bilirubin6) 18 Very common 3.2
Increased AST 15 Very common 3.7
Increased ALT 14 Very common 3.7
Increased alkaline 6.2 Common 0.2
phosphatase**
Drug-induced liver injury7) 0.7 Uncommon 0.7
Skin and subcutaneous tissue disorders
Rash8) 18 Very common 0.5
Photosensitivity 9.1 Common 0.2
Musculoskeletal and connective tissues disorders
Myalgia9) 28 Very common 0.7
Increased blood creatine 10 Very common 3.2
phosphokinase
Renal and urinary disorders
Blood creatinine increased 7.2 Common 0.7*
Acute kidney injury 1.0 Common 1.0*
General disorders and administration site conditions
Oedema10) 30 Very common 0.7
Investigations
Weight increased 12 Very common 0.7
* Includes one Grade 5 event
** Increased alkaline phosphatase was reported in the post-marketing period and in pivotal phase II and phase III
clinical trials.
1)
includes cases of anaemia and haemoglobin decreased
2)
includes cases of dysgeusia and hypogeusia
3)
includes cases of blurred vision, visual impairment, vitreous floaters, reduced visual acuity, asthenopia, and
diplopia
4)
includes cases of bradycardia and sinus bradycardia
5)
includes cases of stomatitis and mouth ulceration
6)
includes cases of blood bilirubin increased, hyperbilirubinaemia and bilirubin conjugated increased
7)
includes two patients with reported MedDRA term of drug-induced liver injury as well as one patient with
reported Grade 4 increased AST and ALT who had documented drug-induced liver injury by liver biopsy
8)
includes cases of rash, rash maculopapular, dermatitis acneiform, erythema, rash generalised, rash papular,
rash pruritic, rash macular and exfoliative rash
9)
includes cases of myalgia and musculoskeletal pain
10)
includes cases of oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema, face
oedema and localised oedema
The safety profile of Alecensa was generally consistent across the pivotal phase III clinical trial
BO28984 (ALEX) and phase II trials (NP28761, NP28673).
Hepatotoxicity
Across clinical trials (NP28761, NP28673, BO28984) two patients with Grade 3-4 AST/ALT
elevations had documented drug induced liver injury by liver biopsy. In addition, one patient
experienced a Grade 4 adverse event of drug-induced liver injury. Two of these cases led to
withdrawal from Alecensa treatment. Adverse reactions of increased AST and ALT levels (15% and
14% respectively) were reported in patients treated with Alecensa across clinical trials (NP28761,
NP28673, BO28984). The majority of these events were of Grade 1 and 2 intensity, and events of
Grade ≥ 3 were reported in 3.7% and 3.7% of the patients, respectively. The events generally occurred
during the first 3 months of treatment, were usually transient and resolved upon temporary interruption
of Alecensa treatment (reported for 1.5% and 3.0% of the patients, respectively) or dose reduction
(2.2% and 1.2%, respectively). In 1.2% and 1.5% of the patients, AST and ALT elevations,
respectively, led to withdrawal from Alecensa treatment. Grade 3 or 4 ALT or AST elevations were
each observed in 5% of patients receiving Alecensa versus 15% and 11% of patients receiving
crizotinib in the phase III clinical trial BO28984.
Adverse reactions of bilirubin elevations were reported in 18% of the patients treated with Alecensa
across clinical trials (NP28761, NP28673, BO28984). The majority of the events were of Grade 1 and
2 intensity; Grade 3 events were reported in 3.2% of the patients. The events generally occurred during
the first 3 months of treatment, were usually transient and the majority resolved upon dose
modification. In 5.2% of patients, bilirubin elevations led to dose modifications and in 1.5% of
patients, bilirubin elevations led to withdrawal from Alecensa treatment. In the phase III clinical trial
BO28984, Grade 3 or 4 bilirubin elevations occurred in 3.3% of patients receiving Alecensa versus no
patient receiving crizotinib.
Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin
greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in one patient
(0.2%) treated in Alecensa clinical trials.
Patients should be monitored for liver function including ALT, AST, and total bilirubin as outlined in
section 4.4 and managed as recommended in section 4.2.
Bradycardia
Cases of bradycardia (8.9%) of Grade 1 or 2 have been reported in patients treated with Alecensa
across clinical trials (NP28761, NP28673, BO28984). No patients had events of Grade ≥ 3 severity.
There were 66 of 365 patients (18%) treated with Alecensa who had post-dose heart rate values below
50 beats per minutes (bpm). In the phase III clinical trial BO28984 15% of patients treated with
Alecensa had post-dose heart rate values below 50 bpm versus 20% of patients treated with crizotinib.
Patients who develop symptomatic bradycardia should be managed as recommended in sections 4.2
and 4.4. No case of bradycardia led to withdrawal from Alecensa treatment.
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of patients receiving crizotinib; and median time to Grade 3 CPK elevation was 27.5 days and 369
days, respectively, in the pivotal phase III clinical trial BO28984 (ALEX).
Gastrointestinal effects
Constipation (35%), nausea (19%), diarrhoea (16%) and vomiting (11%) were the most commonly
reported gastrointestinal (GI) reactions. Most of these events were of mild or moderate severity;
Grade 3 events were reported for diarrhea (0.7%), nausea (0.5%), and vomiting (0.2%). These events
did not lead to withdrawal from Alecensa treatment. Median time to onset for constipation, nausea,
diarrhea, and/or vomiting events across clinical trials (NP28761, NP28673, BO28984) was 21 days.
The events declined in frequency after the first month of treatment. In the phase III clinical trial
BO28984, one patient (0.2%) experienced a Grade 4 event of nausea in the Alecensa arm and the
incidence of Grade 3 and 4 events for nausea, vomiting, and diarrhoea was 3.3%, 3.3%, and 2.0%,
respectively, in the crizotinib arm.
4.9 Overdose
Patients who experience overdose should be closely supervised and general supportive care instituted.
There is no specific antidote for overdose with Alecensa.
5. PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group: anti-neoplastic agents, protein kinase inhibitor; ATC code: L01XE36.
Mechanism of action
Alectinib is a highly selective and potent ALK and RET tyrosine kinase inhibitor. In preclinical
studies, inhibition of ALK tyrosine kinase activity led to blockage of downstream signalling pathways
including STAT 3 and PI3K/AKT and induction of tumour cell death (apoptosis).
Alectinib demonstrated in vitro and in vivo activity against mutant forms of the ALK enzyme,
including mutations responsible for resistance to crizotinib. The major metabolite of alectinib (M4)
has shown similar in vitro potency and activity.
Based on preclinical data, alectinib is not a substrate of p-glycoprotein or BCRP, which are both efflux
transporters in the blood brain barrier, and is therefore able to distribute into and be retained within the
central nervous system.
Treatment-naïve patients
The safety and efficacy of Alecensa were studied in a global randomised Phase III open label clinical
trial (BO28984, ALEX) in ALK-positive NSCLC patients who were treatment naïve. Central testing
for ALK protein expression positivity of tissue samples from all patients by Ventana anti-ALK (D5F3)
immunohistochemistry (IHC) was required before randomisation into the study.
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A total of 303 patients were included in the Phase III trial, 151 patients randomised to the crizotinib
arm and 152 patients randomised to the Alecensa arm receiving Alecensa orally, at the recommended
dose of 600 mg twice daily.
ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no) were
stratification factors for randomisation. The primary endpoint of the trial was to demonstrate
superiority of Alecensa versus crizotinib based on Progression Free survival (PFS) as per investigator
assessment using RECIST 1.1. Baseline demographic and disease characteristics for Alecensa were
median age 58 years (54 years for crizotinib), 55% female (58% for crizotinib), 55% non-Asian (54%
for crizotinib), 61% with no smoking history (65% for crizotinib), 93% ECOG PS of 0 or 1 (93% for
crizotinib), 97% Stage IV disease (96% for crizotinib), 90% adenocarcinoma histology (94% for
crizotinib), 40% CNS metastases at baseline (38% for crizotinib) and 17% having received prior CNS
radiation (14% for crizotinib).
The trial met its primary endpoint at the primary analysis, demonstrating a statistically significant
improvement in PFS by investigator. Efficacy data are summarised in Table 4 and the Kaplan-Meier
curve for investigator assessed PFS is shown in Figure 1.
Crizotinib Alecensa
N=151 N=152
17.6 18.6
Median duration of follow-up (months)
(range 0.3 – 27.0) (range 0.5 – 29.0)
Primary efficacy parameter
PFS (INV)
Number of patients with event n (%) 102 (68%) 62 (41%)
Median (months) 11.1 NE
[95% CI] [9.1; 13.1] [17.7; NE]
HR 0.47
[95% CI] [0.34, 0.65]
Stratified log-rank p-value p <0.0001
PFS (IRC)*
Number of patients with event n (%) 92 (61%) 63 (41%)
Median (months) 10.4 25.7
[95% CI] [7.7; 14.6] [19.9; NE]
HR 0.50
[95% CI] [0.36; 0.70]
Stratified log-rank p-value p < 0.0001
Cause-specific HR 0.16
[95% CI] [0.10; 0.28]
Stratified log-rank p-value p < 0.0001
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Crizotinib Alecensa
N=151 N=152
ORR (INV)*, ***
Responders n (%) 114 (75.5%) 126 (82.9%)
[95% CI] [67.8; 82.1] [76.0; 88.5]
Overall survival*
Number of patients with event n (%) 40 (27%) 35 (23%)
Median (months) NE NE
[95% CI] [NE; NE] [NE; NE]
HR 0.76
[95% CI] [0.48; 1.20]
The PFS benefit was consistent for patients with CNS metastases at baseline (HR = 0.40, 95% CI:
0.25-0.64, median PFS for Alecensa = NE, 95% CI: 9.2-NE, median PFS for crizotinib = 7.4 months,
95%CI: 6.6-9.6) and without CNS metastases at baseline (HR = 0.51, 95% CI: 0.33-0.80, median PFS
for Alecensa = NE, 95% CI: NE, NE, median PFS for crizotinib = 14.8 months, 95% CI:10.8-20.3),
indicating benefit of Alecensa over crizotinib in both subgroups.
13
Figure 1: Kaplan Meier Plot of INV Assessed PFS in BO28984 (ALEX)
The safety and efficacy of Alecensa in ALK-positive NSCLC patients pre-treated with crizotinib were
studied in two Phase I/II clinical trials (NP28673 and NP28761).
NP28673
Study NP28673 was a Phase I/II single arm, multicentre study conducted in patients with
ALK-positive advanced NSCLC who have previously progressed on crizotinib treatment. In addition
to crizotinib, patients may have received previous treatment with chemotherapy. A total of
138 patients were included in the phase II part of the study and received Alecensa orally, at the
recommended dose of 600 mg twice daily.
The primary endpoint was to evaluate the efficacy of Alecensa by Objective Response Rate (ORR) as
per central Independent Review Committee (IRC) assessment using Response Evaluation Criteria in
Solid Tumors (RECIST) version 1.1 in the overall population (with and without prior exposure of
cytotoxic chemotherapy treatments). The co-primary endpoint was to evaluate the ORR as per central
IRC assessment using RECIST 1.1 in patients with prior exposure of cytotoxic chemotherapy
treatments. A lower confidence limit for the estimated ORR above the pre-specified threshold of 35%
would achieve a statistically significant result.
Patient demographics were consistent with that of a NSCLC ALK positive population. The
demographic characteristics of the overall study population were 67% Caucasian, 26% Asian, 56%
females, and the median age was 52 years. The majority of patients had no history of smoking (70%).
The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 or 1 in 90.6%
of patients and 2 in 9.4% of patients. At the time of entry in the study, 99% of patients had stage IV
disease, 61% had brain metastases and in 96% of patients tumours were classified as adenocarcinoma.
Among patients included in the study, 20% of the patients had previously progressed on crizotinib
treatment only, and 80% had previously progressed on crizotinib and at least one chemotherapy
treatment.
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Study NP28761
Study NP28761 was a Phase I/II single arm multicentre study conducted in patients with ALK positive
advanced NSCLC who have previously progressed on crizotinib treatment. In addition to crizotinib,
patients may have received previous treatment with chemotherapy. A total of 87 patients were
included in the phase II part of the study and received Alecensa orally, at the recommended dose of
600 mg twice daily.
The primary endpoint was to evaluate the efficacy of Alecensa by ORR as per central IRC assessment
using RECIST version 1.1. A lower confidence limit for the estimated ORR above the pre-specified
threshold of 35% would achieve a statistically significant result.
Patient demographics were consistent with that of a NSCLC ALK positive population. The
demographic characteristics of the overall study population were 84% Caucasian, 8% Asian, 55%
females. The median age was 54 years. The majority of patients had no history of smoking (62%). The
ECOG performance status at baseline was 0 or 1 in 89.7% of patients and 2 in 10.3% of patients. At
the time of entry in the study, 99% of patients had stage IV disease, 60% had brain metastases and in
94% of patients tumours were classified as adenocarcinoma. Among the patients included in the study,
26% of the patients had previously progressed on crizotinib treatment only, and 74% had previously
progressed on crizotinib and at least one chemotherapy treatment.
The main efficacy results from studies NP28673 and NP28761 are summarised in Table 5. A summary
of pooled analysis of CNS endpoints is presented in Table 6.
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Table 5 Efficacy results from studies NP28673 and NP28761
NP28673 NP28761
Alecensa 600 mg Alecensa 600 mg
twice daily twice daily
21 17
Median duration of follow-up (months)
(range 1 – 30) (range 1 – 29)
Primary efficacy parameters
DOR (IRC) N = 62 N = 35
Number of patients with events N (%) 36 (58.1%) 20 (57.1%)
Median (months) 15.2 14.9
[95% CI] [11.2, 24.9] [6.9, NE]
CI = confidence interval; DOR = duration of response; IRC = independent review committee; NE = not
estimable; ORR = objective response rate; PFS= progression free survival; RE = response evaluable
a
16 patients did not have measurable disease at baseline according to the IRC and were not included in the IRC
response evaluable population.
b
20 patients did not have measurable disease at baseline according to the IRC and were not included in the IRC
response evaluable population
ORR results for studies NP28673 and NP28761 were consistent across subgroups of baseline patient
characteristics such as age, gender, race, ECOG performance status, Central Nervous System (CNS)
metastasis and prior chemotherapy use, especially when considering the small number of patients in
some subgroups.
16
Table 6 Summary of the pooled analysis of CNS endpoints from studies NP28673 and NP28761
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Alecensa in all subsets of the paediatric population in lung carcinoma (small cell and non-small cell
carcinoma) (see section 4.2 for information on paediatric use).
The pharmacokinetic parameters for alectinib and its major active metabolite (M4) have been
characterised in ALK-positive NSCLC patients and healthy subjects. Based on population
pharmacokinetic analysis, the geometric mean (coefficient of variation %) steady-state Cmax, Cmin and
AUC0-12hr for alectinib were approximately 665 ng/mL (44.3%), 572 ng/mL (47.8%) and 7430
ng*h/mL (45.7%), respectively. The geometric mean steady-state Cmax, Cmin and AUC0-12hr for M4
were approximately 246 ng/mL (45.4%), 222 ng/mL (46.6%) and 2810 ng*h/mL (45.9%),
respectively.
Absorption
Following oral administration of 600 mg twice daily under fed conditions in ALK-positive NSCLC
patients, alectinib was absorbed reaching Tmax after approximately 4 to 6 hours.
Alectinib steady-state is reached within 7 days with continuous 600 mg twice daily dosing. The
accumulation ratio for the twice-daily 600 mg regimen was approximately 6-fold. Population PK
analysis supports dose proportionality for alectinib across the dose range of 300 to 900 mg under fed
conditions.
The absolute bioavailability of alectinib capsules was 36.9% (90% CI: 33.9%, 40.3%) under fed
conditions in healthy subjects.
Following a single oral administration of 600 mg with a high-fat, high-calorie meal, alectinib and M4
exposure was increased by around 3-fold relative to fasted conditions (see section 4.2).
Distribution
Alectinib and its major metabolite M4 are highly bound to human plasma proteins (>99%),
independent of active substance concentration. The mean in vitro human blood-to-plasma
concentration ratios of alectinib and M4 are 2.64 and 2.50, respectively, at clinically relevant
concentrations.
The geometric mean volume of distribution at steady state (Vss) of alectinib following IV
administration was 475 L, indicating extensive distribution into tissues.
17
Based on in vitro data, alectinib is not a substrate of P-gp. Alectinib and M4 are not substrates of
BCRP or organic anion-transporting polypeptide (OATP) 1B1/B3.
Biotransformation
In vitro metabolism studies showed that CYP3A4 is the main CYP isozyme mediating alectinib and its
major metabolite M4 metabolism, and is estimated to contribute 40-50% of alectinib metabolism.
Results from the human mass balance study demonstrated that alectinib and M4 were the main
circulating moieties in plasma with 76% of the total radioactivity in plasma. The geometric mean
Metabolite/Parent ratio at steady state is 0.399.
Metabolite M1b was detected as a minor metabolite from in vitro and in human plasma in healthy
subjects. Formation of metabolite M1b and its minor isomer M1a is likely to be catalyzed by a
combination of CYP isozymes (including isozymes other than CYP3A) and aldehyde dehydrogenase
(ALDH) enzymes.
In vitro studies indicate that neither alectinib nor its major active metabolite (M4) inhibits CYP1A2,
CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Alectinib did not
inhibit OATP1B1/OATP1B3, OAT1, OAT3 or OCT2 at clinically relevant concentrations in vitro.
Elimination
Following administration of a single dose of 14C-labeled alectinib administered orally to healthy
subjects the majority of radioactivity was excreted in faeces (mean recovery 97.8%) with minimal
excretion in urine (mean recovery 0.46%). In faeces, 84% and 5.8% of the dose was excreted as
unchanged alectinib or M4, respectively.
Based on a population PK analysis, the apparent clearance (CL/F) of alectinib was 81.9 L/hour. The
geometric mean of the individual elimination half-life estimates for alectinib was 32.5 hours. The
corresponding values for M4 were 217 L/hour and 30.7 hours, respectively.
Renal impairment
Negligible amounts of alectinib and the active metabolite M4 are excreted unchanged in urine (< 0.2%
of the dose). Based on a population pharmacokinetic analysis alectinib and M4 exposures were similar
in patients with mild and moderate renal impairment and normal renal function. The pharmacokinetics
of alectinib has not been studied in patients with severe renal impairment.
Hepatic impairment
As elimination of alectinib is predominantly through metabolism in the liver, hepatic impairment may
increase the plasma concentration of alectinib and/or its major metabolite M4. Based on a population
pharmacokinetic analysis, alectinib and M4 exposures were similar in patients with mild hepatic
impairment and normal hepatic function.
Following administration of a single oral dose of 300 mg alectinib in subjects with severe (Child-Pugh
C) hepatic impairment, alectinib Cmax was the same and AUCinf was 2.2-fold higher compared with the
same parameters in matched healthy subjects. M4 Cmax and AUCinf was 39% and 34% lower
respectively, resulting in a combined exposure of alectinib and M4 (AUCinf) 1.8-fold higher in patients
with severe hepatic impairment compared with matched healthy subjects.
The hepatic impairment study also included a group with moderate (Child-Pugh B) hepatic
impairment, and a modestly higher alectinib exposure was observed in this group compared with
matched healthy subjects. The subjects in the Child Pugh B group however did in general not suffer
from abnormal bilirubin, albumin or prothrombin time, indicating that they may not be fully
representative of moderately hepatically impaired subjects with decreased metabolic capacity.
18
Effects of age, body weight, race and gender
Age, body weight, race and gender had no clinically meaningful effect on the systemic exposure of
alectinib and M4. The range of body weights for patients enrolled in clinical studies is 36.9-123 kg.
There are no available data on patients with extreme body weight (>130 kg) (see section 4.2).
Carcinogenicity
Carcinogenicity studies have not been performed to establish the carcinogenic potential of Alecensa.
Mutagenicity
Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but induced a
slight increase in numerical aberrations in the in vitro cytogenetic assay using Chinese Hamster Lung
(CHL) cells with metabolic activation, and micronuclei in a rat bone marrow micronucleus test. The
mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity), and not
a clastogenic effect on chromosomes.
Impairment of fertility
No fertility studies in animals have been performed to evaluate the effect of Alecensa. No adverse
effects on male and female reproductive organs were observed in general toxicology studies. These
studies were conducted in rats and monkeys at exposures equal to or greater than 2.6- and 0.5-fold,
respectively, of the human exposure, measured by AUC, at the recommended dose of 600 mg twice
daily.
Teratogenicity
Alectinib caused embryo-foetal toxicity in pregnant rats and rabbits. In pregnant rats, alectinib caused
total embryo-foetal loss (miscarriage) at exposures 4.5-fold of the human AUC exposure and small
foetuses with retarded ossification and minor abnormalities of the organs at exposures 2.7-fold of the
human AUC exposure. In pregnant rabbits, alectinib caused embryo-foetal loss, small fetuses and
increased incidence of skeletal variations at exposures 2.9-fold of the human AUC exposure at the
recommended dose.
Other
Alectinib absorbs UV light between 200 and 400 nm and demonstrated a phototoxic potential in an in
vitro photosafety test in cultured murine fibroblasts after UVA irradiation.
Target organs in both rat and monkey at clinically relevant exposures in the repeat-dose toxicology
studies included, but were not limited to the erythroid system, gastrointestinal tract, and hepatobiliary
system.
Abnormal erythrocyte morphology was observed at exposures equal or greater than 10-60% the
human exposure by AUC at the recommended dose. Proliferative zone extension in GI mucosa in both
species was observed at exposures equal to or greater than 20-120% of the human AUC exposure at
the recommended dose. Increased hepatic alkaline phosphatase (ALP) and direct bilirubin as well as
vacuolation/degeneration/necrosis of bile duct epithelium and enlargement/focal necrosis of
hepatocytes was observed in rats and/or monkeys at exposures equal to or greater than 20-30% of the
human exposure by AUC at the recommended dose.
A mild hypotensive effect has been observed in monkeys at around clinically relevant exposures.
19
6. PHARMACEUTICAL PARTICULARS
Capsule content
Lactose monohydrate
Hydroxypropylcellulose
Sodium laurilsulfate
Magnesium stearate
Carmellose calcium
Capsule shell
Hypromellose
Carrageenan
Potassium chloride
Titanium dioxide (E171)
Maize starch
Carnauba wax
Printing ink
Red iron oxide (E172)
Yellow iron oxide (E172)
Indigo carmine aluminum lake (E132)
Carnauba wax
White shellac
Glyceryl monooleate
6.2 Incompatibilities
Not applicable.
3 years.
Blisters:
Store in the original package in order to protect from moisture.
Bottles:
Store in the original package and keep the bottle tightly closed in order to protect from moisture.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
20
7. MARKETING AUTHORISATION HOLDER
EU/1/16/1169/001
EU/1/16/1169/002
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
21
ANNEX II
22
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
The requirements for submission of periodic safety update reports for this medicinal product are set
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and any subsequent updates published on the European medicines web-portal.
The marketing authorisation holder shall submit the first periodic safety update report for this product
within 6 months following authorisation.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreeed subsequent
updates of the RMP.
23
ANNEX III
24
A. LABELLING
25
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
Contains lactose and sodium. See package leaflet for further information.
Hard capsule
Oral use
Read the package leaflet before use
8. EXPIRY DATE
EXP
26
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/16/1169/001
Batch
alecensa
PC:
SN:
NN:
27
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
Contains lactose and sodium. See package leaflet for further information.
Hard capsule
56 hard capsules
Oral use
Read the package leaflet before use
8. EXPIRY DATE
EXP
28
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/16/1169/001
Batch
alecensa
29
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
30
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
Contains lactose and sodium. See package leaflet for further information.
Hard capsule
Oral use
Read the package leaflet before use
8. EXPIRY DATE
EXP
Store in the original package and keep the bottle tightly closed in order to protect from moisture
31
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/16/1169/002
Batch
alecensa
PC:
SN:
NN:
32
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL
3. LIST OF EXCIPIENTS
Contains lactose and sodium. See package leaflet for further information.
Hard capsule
Oral use
Read the package leaflet before use
8. EXPIRY DATE
EXP
Store in the original package and keep the bottle tightly closed in order to protect from moisture
33
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/16/1169/002
Batch
34
B. PACKAGE LEAFLET
35
Package leaflet: Information for the patient
This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.
Read all of this leaflet carefully before you start taking this medicine - because it contains
important information for you.
What Alecensa is
Alecensa is a cancer medicine that contains the active substance alectinib.
Alecensa can be prescribed to you as first treatment of your lung cancer, or if you have been
previously treated with a medicine containing ‘crizotinib’.
If you have any questions about how Alecensa works or why this medicine has been prescribed for
you, ask your doctor, pharmacist or nurse.
36
2. What you need to know before you take Alecensa
Alecensa can cause side effects that you need to tell your doctor about straight away. These include:
● liver injury (hepatotoxicity). Your doctor will take blood tests before you start treatment, then
every 2 weeks for the first 3 months of your treatment and then less often. This is to check you do
not have any liver problems while taking Alecensa. Tell your doctor straight away if you get any of
the following signs: yellowing of your skin or the whites of your eyes, pain on the right side of
your stomach area, dark urine, itchy skin, feeling less hungry than usual, nausea or vomiting,
feeling tired, bleeding or bruising more easily than normal.
● slow heart beat (bradycardia).
● lung inflammation (pneumonitis). Alecensa may cause severe or life-threatening swelling
(inflammation) of the lungs during treatment. The signs may be similar to those from your lung
cancer. Tell your doctor straight away if you have any new or worsening signs including difficulty
in breathing, shortness of breath, or cough with or without mucous, or fever.
● severe muscle pain, tenderness, and weakness (myalgia). Your doctor will do blood tests at least
every 2 weeks for the first month and as needed during treatment with Alecensa. Tell your doctor
straight away if you get new or worsening signs of muscle problems, including unexplained muscle
pain or muscle pain that does not go away, tenderness, or weakness.
Look out for these while you are taking Alecensa. See ‘Side effects’ in section 4 for more information.
Sensitivity to sunlight
Do not expose yourself to the sun for any long period of time while you are taking Alecensa and for
7 days after you stop. You need to apply sunscreen and lip balm with a Sun Protection Factor of 50 or
higher to help prevent sunburn.
In particular tell your doctor or pharmacist if you are taking any of the following medicines:
● digoxin, a medicine used to treat heart problems
● dabigatran etexilate, a medicine used to treat blood clots
● methotrexate, a medicine used to treat certain types of cancer or to treat autoimmune diseases (e.g.
rheumatoid arthritis)
37
● nilotinib, a medicine used to treat certain types of cancer
● lapatinib, a medicine used to treat certain types of breast cancer
● mitoxantrone, a medicine used to treat certain types of cancer or autoimmune diseases (e.g.
multiple sclerosis)
● everolimus, a medicine used to treat certain types of cancer or used to prevent the body’s immune
system from rejecting a transplanted kidney, heart or liver
● sirolimus, a medicine used to prevent the body’s immune system from rejecting a transplanted
kidney, heart or liver
● topotecan, a medicine used to treat certain types of cancer
● medicines used to treat AIDS/HIV (e.g. ritonavir, saquinavir)
● medicines used to treat infections. These include medicines that treat fungal infections (antifungals
such as ketoconazole, itraconazole, voriconazole, posaconazole) and medicines that treat certain
types of bacterial infection (antibiotics such as telithromycin)
● St. John’s Wort, a herbal medicine used to treat depression
● medicines used to stop seizures or fits (anti-epileptics such as phenytoin, carbamazepine, or
phenobarbital)
● medicines used to treat tuberculosis (e.g. rifampicin, rifabutin)
● nefazodone, a medicine used to treat depression
Oral contraceptives
If you take Alecensa whilst using oral contraceptives, the oral contraceptives may be less effective.
Pregnancy
● Do not take Alecensa if you are pregnant. This is because it may harm your baby.
● If you become pregnant when taking the medicine or during the 3 months after taking your last
dose, tell your doctor straight away.
Breast-feeding
● Do not breast-feed while taking this medicine. This is because it is not known if Alecensa can
pass over into breast milk and could therefore harm your baby.
38
3. How to take Alecensa
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor,
pharmacist or nurse if you are not sure.
If you have severe liver problems before starting your treatment with Alecensa:
● The recommended dose is 3 capsules (450 mg) twice a day.
● This means you take a total of 6 capsules (900 mg) each day.
Sometimes your doctor may lower your dose, stop your treatment for a short time or stop your
treatment completely if you feel unwell.
How to take
● Alecensa is taken by mouth. Swallow each capsule whole. Do not open or dissolve the capsules.
● You must take Alecensa with food.
Like all medicines, this medicine can cause side effects, although not everybody gets them. The
following side effects may happen with this medicine.
39
● New or worsening signs including difficulty in breathing, shortness of breath, or cough with or
without mucous, or fever - the signs may be similar to those from your lung cancer (potential
signs of lung inflammation – pneumonitis). Alecensa can cause severe or life-threatening
inflammation of the lungs during treatment.
40
6. Contents of the pack and other information
The capsules are provided in blisters and are available in cartons containing 224 hard capsules
(4 packs of 56). The capsules are also available in plastic bottles containing 240 hard capsules.
Manufacturer
Roche Pharma AG
Emil-Barell-Strasse 1
D-79639 Grenzach-Wyhlen
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien Lietuva
N.V. Roche S.A. UAB “Roche Lietuva”
Tél/Tel: +32 (0) 2 525 82 11 Tel: +370 5 2546799
България Luxembourg/Luxemburg
Рош България ЕООД (Voir/siehe Belgique/Belgien)
Тел: +359 2 818 44 44
Danmark Malta
Roche a/s (See Ireland)
Tlf: +45 - 36 39 99 99
41
Deutschland Nederland
Roche Pharma AG Roche Nederland B.V.
Tel: +49 (0) 7624 140 Tel: +31 (0) 348 438050
Eesti Norge
Roche Eesti OÜ Roche Norge AS
Tel: + 372 - 6 177 380 Tlf: +47 - 22 78 90 00
Ελλάδα Österreich
Roche (Hellas) A.E. Roche Austria GmbH
Τηλ: +30 210 61 66 100 Tel: +43 (0) 1 27739
España Polska
Roche Farma S.A. Roche Polska Sp.z o.o.
Tel: +34 - 91 324 81 00 Tel: +48 - 22 345 18 88
France Portugal
Roche Roche Farmacêutica Química, Lda
Tél: +33 (0) 1 47 61 40 00 Tel: +351 - 21 425 70 00
Hrvatska România
Roche d.o.o. Roche România S.R.L.
Tel: +385 1 4722 333 Tel: +40 21 206 47 01
Ireland Slovenija
Roche Products (Ireland) Ltd. Roche farmacevtska družba d.o.o.
Tel: +353 (0) 1 469 0700 Tel: +386 - 1 360 26 00
Italia Suomi/Finland
Roche S.p.A. Roche Oy
Tel: +39 - 039 2471 Puh/Tel: +358 (0) 10 554 500
Kύπρος Sverige
Γ.Α.Σταμάτης & Σια Λτδ. Roche AB
Τηλ: +357 - 22 76 62 76 Tel: +46 (0) 8 726 1200
42